Benzothiazepine derivatives for the treatment of hyperlipidemia

ABSTRACT

The present invention relates to compounds of formula (I): wherein variable groups are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidemia. Processes for their manufacture and pharmaceutical compositions containing them are also described

This application is a national stage filing under 35 U.S.C. 371 ofInternational Application No. PCT/GB02/04043, filed Sep. 5, 2002, whichclaims priority from GB Application No. GB 0121621.7, filed Sep. 7,2001, the specification of each of which are incorporated by referenceherein. International Application No. PCT/ GB02/04043 was publishedunder PCT Article 21(2) in English.

This invention relates to benzothiazepine derivatives, orpharmaceutically acceptable salts, solvates, solvates of such salts andprodrugs thereof These benzothiazepines possess ileal bile acidtransport (IBAT) inhibitory activity and accordingly have value in thetreatment of disease states associated with hyperlipidaemic conditionsand they are useful in methods of treatment of a warm-blooded animal,such as man. The invention also relates to processes for the manufactureof said benzothiazepine derivatives, to pharmaceutical compositionscontaining them and to their use in the manufacture of medicaments toinhibit IBAT in a warm-blooded animal, such as man.

It is well-known that hyperlipidaemic conditions associated withelevated concentrations of total cholesterol and low-density lipoproteincholesterol are major risk factors for cardiovascular atheroscleroticdisease (for instance “Coronary Heart Disease: Reducing the Risk; aWorldwide View” Assman G., Carmena R. Cullen P. et al; Circulation 1999,100, 1930–1938 and “Diabetes and Cardiovascular Disease: A Statement forHealthcare Professionals from the American Heart Association” Grundy S,Benjamin I., Burke G., et al; Circulation, 1999, 100, 1134–46).Interfering with the circulation of bile acids within the lumen of theintestinal tracts is found to reduce the level of cholesterol. Previousestablished therapies to reduce the concentration of cholesterolinvolve, for instance, treatment with HMG-CoA reductase inhibitors,preferably statins such as simvastatin and fluvastatin, or treatmentwith bile acid binders, such as resins. Frequently used bile acidbinders are for instance cholestyramine and cholestipol. One recentlyproposed therapy (“Bile Acids and Lipoprotein Metabolism: a Renaissancefor Bile Acids in the Post Statin Era” Angelin B, Eriksson M, Rudling M;Current Opinion on Lipidology, 1999, 10, 269–74) involved the treatmentwith substances with an IBAT inhibitory effect.

Re-absorption of bile acid from the gastro-intestinal tract is a normalphysiological process which mainly takes place in the ileum by the IBATmechanism. Inhibitors of IBAT can be used in the treatment ofhypercholesterolaemia (see for instance “Interaction of bile acids andcholesterol with nonsystemic agents having hypocholesterolaemicproperties”, Biochemica et Biophysica Acta, 1210 (1994) 255–287). Thus,suitable compounds having such inhibitory IBAT activity are also usefulin the treatment of hyperlipidaemic conditions. Compounds possessingsuch IBAT inhibitory activity have been described, see for instance thecompounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO 98/38182, WO99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO01/68906, WO 01/66533, WO 02/50051 and EP 0 864 582.

A further aspect of this invention relates to the use of the compoundsof the invention in the treatment of dyslipidemic conditions anddisorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). Inaddition, these compounds are expected to be useful for the preventionand treatment of different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocytes, monocytes and/or macrophage infiltration, intimalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks.

The present invention is based on the discovery that certainbenzothiazepine compounds surprisingly inhibit IBAT. Such properties areexpected to be of value in the treatment of disease states associatedwith hyperlipidaemic conditions.

Accordingly, the present invention provides a compound of formula (I):

wherein:

One of R¹ and R² are selected from hydrogen C₁₋₆alkyl or C₂₋₆alkenyl andthe other is selected from C₁₋₆alkyl or C₂₋₆alkenyl;

R^(y) is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₄alkoxy andC₁₋₆alkanoyloxy;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB):

wherein:

Y is —N(R^(x))—, —N(R^(x))C(O)—, —O—, and —S(O)a—; wherein a is 0–2 andR^(x) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₆alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl; or R¹⁵ is agroup of formula (IC):

wherein:

R²⁴ is selected from hydrogen or C₁₋₄alkyl;

R²⁵ is selected from hydrogen, C₁₋₄alkyl, carbocyclyl, heterocyclyl orR²⁷; wherein said C₁₋₄alkyl, carbocyclyl or heterocyclyl may beindependently optionally substituted by one or more substituentsselected from R²⁸;

R²⁶ is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl,—P(O)(OR^(g))(OR^(b)), —P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or—P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) are independently selectedfrom C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

z is 0–3; wherein the values of R²⁵ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²⁷ and R²⁸ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, sulpho, sulphino, amidino, (C₁₋₄alkyl)₃silyl, phosphono,—P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selectedfrom C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may be independently optionallysubstituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further feature of the present invention there isprovided a compound of formula (I):

wherein:

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(y) is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₄alkoxy andC₁₋₆alkanoyloxy,

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkly, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB):

wherein:

Y is —N(R^(x))—, —N(R^(x))C(O)—, —O—, and —S(O)a—; wherein a is 0–2 andR^(x) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹ and R²⁰ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl,N,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may beindependently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, alkyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” includes C₁₋₄alkyl, propyl, isopropyl and t-butyl.However, references to individual alkyl groups such as ‘propyl’ arespecific for the straight chained version only and references toindividual branched chain alkyl groups such as ‘isopropyl’ are specificfor the branched chain version only. A similar convention applies toother radicals, for example “phenylC₁₋₆alkyl” would includephenylC₁₋₆alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term“halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

“Heteroaryl” is a totally unsaturated, mono or bicyclic ring containing3–12 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. Preferably “heteroaryl” refers to a totally unsaturated,monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. Examples and suitable values of the term “heteroaryl” arethienyl, isoxazolyl, imidazolyl, pyrrolyl, thiadiazolyl, isothiazolyl,triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyland quinolyl. Preferably the term “heteroaryl” refers to thienyl orindolyl.

“Aryl” is a totally unsaturated, mono or bicyclic carbon ring thatcontains 3–12 atoms. Preferably “aryl” is a monocyclic ring containing 5or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable valuesfor “aryl” include phenyl or naphthyl. Particularly “aryl” is phenyl.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 3–12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)— or a ring sulphur atom may beoptionally oxidised to form the S-oxides. Preferably a “heterocyclyl” isa saturated, partially saturated or unsaturated, mono or bicyclic ringcontaining 5 or 6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen, which may, unless otherwise specified, becarbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)— or a ring sulphur atom may be optionally oxidisedto form S-oxide(s). Examples and suitable values of the term“heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl,1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl,1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino,1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl,homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl,indolyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3–12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Preferably “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.Particularly “carbocyclyl” is cyclopropyl, cyclobutyl, 1-oxocyclopentyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or1-oxoindanyl.

An example of “C₁₋₆alkanoyloxy” and “C₁₋₄alkanoyloxy” is acetoxy.Examples of “C₁₋₆alkoxycarbonyl” and “C₁₋₄alkoxycarbonyl” includemethoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁₋₄alkoxy” “C₁₋₄alkoxy” include methoxy, ethoxy and propoxy. Examplesof “C₁₋₆alkanoylamino” and “C₁₋₄alkanoylamino” include formamido,acetamido and propionylamino. Examples of “C₁₋₆alkylS(O)_(a) wherein ais 0 to 2” and “C₁₋₄alkylS(O)_(a) wherein a is 0 to 2” includemethylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl andethylsulphonyl. Examples of “C₁₋₆alkanoyl” and “C₁₋₄alkanoyl” includepropionyl and acetyl. Examples of “N—(C₁₋₆alkyl)amino” and“N—(C₁₋₄alkyl)amino” include methylamino and ethylamino. Examples of“N,N—(C₁₋₆alkyl)₂amino” and “N,N—(C₁₋₄alkyl)₂amino” includedi-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examplesof “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₆alkynyl” and “C₂₋₄alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” and“N—(C₁₋₄alkyl)sulphamoyl” are N-(methyl)sulphamoyl andN-(ethyl)sulphamoyl. Examples of “N—(C₁₋₆alkyl)₂sulphamoyl” and“N—(C₁₋₄alkyl)₂sulphamoyl” are N,N-(dimethyl)sulphamoyl andN-(methyl)-N-(ethyl)sulphamoyl. Examples of “N—(C₁₋₆alkyl)carbamoyl” and“N—(C₁₋₄alkyl)carbamoyl” are methylaminocarbonyl and ethylaminocarbonyl.Examples of “N,N—(C₁₋₆alkyl)₂carbamoyl” and “N,N—(C₁₋₄alkyl)₂carbamoyl”are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of“(C₁₋₄alkyl)₃silyl,” include trimethylsilyl and methyldiethylsilyl.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric, acetate or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). examples of pro-drugs include in vivohydrolysable esters and in vivo hydrolysable amides of a compound of theformula (I).

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an in vivo hydrolysable amide of a compound of theformula (I) containing a carboxy group is, for example, a N—C₁₋₆alkyl orN,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess IBAT inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess IBAT inhibitory activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess IBAT inhibitory activity.

Particular values are as follows. Such values maybe used whereappropriate with any of the definitions, claims or embodiments definedhereinbefore or hereinafter.

R¹ and R² are C₁₋₄alkyl.

R¹ and R² are butyl.

One of R¹ and R² is ethyl and the other is butyl.

One of R¹ and R² is ethyl and the other is butyl or R¹ and R² are bothbutyl.

v is 0 or 1.

v is 0.

R^(z) is C₁₋₄alkyl.

R^(y) is hydrogen.

R^(y) is hydrogen or hydroxy.

R³ and R⁶ are hydrogen.

R⁴ is methylthio.

R⁴ is hydrogen.

R⁴ is hydrogen, halo or C₁₋₄alkylS(O)_(a) wherein a is 0.

R⁴ is hydrogen, bromo or methylthio.

R⁵ is a group of formula (IA) (as depicted above) wherein:

X is —O—;

n is 1;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

m is 0; and

R¹¹ is carboxy.

R⁵ is N-((R)-α-carboxybenzyl)carbamoylmethoxy.

R⁵ is a group of formula (IA) (as depicted above); wherein

X is —O—;

Ring A is aryl; wherein Ring A is optionally substituted by one or moresubstituents selected from R¹⁷;

R⁷is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

R¹¹ is carboxy; or R¹¹ is a group of formula (IB) (as depicted above);wherein:

R¹² is hydrogen;

R¹³ is hydrogen;

R¹⁵ is carboxy or sulpho;

p is 1 or 2;

q is 0;

r is 0;

m is 0;

n is 1; and

R¹⁷ is hydroxy.

R⁵ is a group of formula (IA) (as depicted above); wherein

X is —O—;

Ring A is phenyl or 4-hydroxyphenyl;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

R¹¹ is carboxy; or R¹¹ is a group of formula (IB) (as depicted above);wherein:

R¹² is hydrogen;

R¹³ is hydrogen;

R¹⁵ is carboxy or sulpho;

p is 1 or 2;

q is 0;

r is 0;

m is 0; and

n is 1;

R⁵ is N-((R)-α-carboxybenzyl)carbamoylmethoxy,N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy; orN-{(R)-α-[N-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy.

Therefore in one aspect of the invention there is provided a compound offormula (I) (as depicted above)

R¹ and R² are C₁₋₄alkyl;

v is 0;

R^(y) is hydrogen or hydroxy;

R³ and R⁶ are hydrogen;

R⁴ is hydrogen, halo or C₁₋₄alkylS(O)_(a) wherein a is 0;

R⁵ is a group of formula (IA) (as depicted above); wherein

X is —O—;

Ring A is aryl; wherein Ring A is optionally substituted by one or moresubstituents selected from R¹⁷;

R⁷ is hydrogen;

R⁸ is hydrogen;

R⁹ is hydrogen;

R¹¹ is carboxy; or R¹¹ is a group of formula (IB) (as depicted above);wherein:

R¹² is hydrogen;

R¹³ is hydrogen;

R¹⁵ is carboxy or sulpho;

p is 1 or 2;

q is 0;

r is 0;

m is 0;

n is 1; and

R¹⁷ is hydroxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in one aspect of the invention there is provided a compound offormula (I) (as depicted above)

One of R¹ and R² is ethyl and the other is butyl;

v is 0;

R^(y) is hydrogen or hydroxy;

R³ and R⁶ are hydrogen;

R⁴ is hydrogen, bromo or methylthio;

R⁵ is N-((R)-α-carboxybenzyl)carbamoylmethoxy;N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy; orN-{(R)-α-[N-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the examples or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

Preferred aspects of the invention are those which relate to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof which process(wherein variable groups are, unless otherwise specified, as defined informula (I)) comprises of:

-   Process 1): oxidising a benzothiazepine of formula (II):

-   Process 2): for compounds of formula (I) wherein X is —O—, —NR^(a)    or —S—; reacting a compound of formula (IIIa) or (IIIb):

with a compound of formula (IV):

wherein L is a displaceable group;

-   Process 3): reacting an acid of formula (Va) or (Vb):

or an activated derivative thereof; with an amine of formula (VI):

-   Process 4): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB); reacting a compound of formula (I) wherein R¹¹ is    carboxy with an amine of formula (VII):

-   Process 5): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and R¹⁵ is a group of formula (IC) reacting a compound    of formula (I) wherein R¹⁵ is carboxy with an amine of formula    (VIII):

-   Process 6) for compounds of formula (I) wherein one of R⁴ and R⁵ are    independently selected from C₁₋₆alkylthio optionally substituted on    carbon by one or more R¹⁶; reacting a compound of formula (IXa) or    (IXb):

wherein L is a displaceable group; with a thiol of formula (X):R^(m)—H  (X)wherein R^(m) is C₁₋₆alkylthio optionally substituted on carbon by oneor more R¹⁶;

-   Process 7): for compounds of formula (I) wherein R¹¹ is carboxy;    deprotecting a compound of formula (XIa):

wherein R^(x) together with the —OC(O)— group to which it is attachedforms an ester;

-   Process 8): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and R¹⁵ is carboxy; deprotecting a compound of formula    (XIIa):

wherein R^(x) together with the —OC(O)— group to which it is attachedforms an ester;

-   Process 9): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and Y is —N(R^(x))C(O)—; reacting an acid of formula    (XIIIa):

or an activated derivative thereof; with an amine of formula (XIV):

-   or Process 10): for compounds of formula (I) wherein R¹¹ is a group    of formula (IB), R¹⁵ is a group of formula (IC) and R²⁶ is carboxy,    deprotecting a compound of formula (XVa):

wherein R^(x) together with the —OC(O)— group to which it is attachedforms an ester; and thereafter if necessary or desirable:

-   i) converting a compound of the formula (I) into another compound of    the formula (I);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt, solvate, solvate of    such a salt or a prodrug.

L is a displaceable group, suitable values for L are for example, ahalogeno or sulphonyloxy group, for example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

R^(x) together with the —OC(O)— group to which it is attached forms anester. Preferably R^(x) is methyl or ethyl. More preferably R^(x) ismethyl. In another aspect of the invention R^(x) is C₁₋₆alkyl orphenylC₁₋₆alkyl, preferably C₁₋₄alkyl or benzyl, more preferablyt-butyl, methyl, ethyl or benzyl.

Specific reaction conditions for the above reactions are as follows.

-   Process 1): Benzothiazepines of formula (II) may be oxidised under    standard sulphur oxidation conditions; for example using hydrogen    peroxide and trifluoroacetic acid at a temperature in the range of    0° C. to reflux, preferably at or near room temperature.

Compounds of formula (II) may be prepared according to Scheme I:

Compounds of formula (IIa), (IIb) and (IIf) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

-   Process 2): Compounds of formula (IIIa) or (IIIb) may be reacted    with compounds of formula (IV) in the presence of a base for example    an inorganic base such as sodium carbonate, or an organic base such    as Hunigs base, in the presence of a suitable solvent such as    acetonitrile, dichloromethane or tetrahydrofuran at a temperature in    the range of 0° C. to reflux, preferably at or near reflux.

Compounds of formula (IIIa) or (IIIb) may be prepared in a similarmanner to compounds of formula (II) but wherein R⁴ or R⁵ is —OH,—NH(R^(a)) or —SH (optionally for —SO— and —SO₂— followed by theoxidation step of Process 1). Compounds of formula (IIIa) or (IIIb)wherein X is —O— or —S— may also be prepared by the procedures disclosedin WO 9605188.

Compounds of formula (IV) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

-   Process 3) and Process 4) and Process5) and Process 9): Acids and    amines may be coupled together in the presence of a suitable    coupling reagent. Standard peptide coupling reagents known in the    art can be employed as suitable coupling reagents, or for example    carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the    presence of a catalyst such as dimethylaminopyridine or    4-pyrrolidinopyridine, optionally in the presence of a base for    example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as    2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include    dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and    dimethylformamide. The coupling reaction may conveniently be    performed at a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for exampleacid chlorides, and active esters, for example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

Compounds of formula (Va) or (Vb) wherein X═—O—,—NR^(a),—S— may beprepared according to Scheme 2:

Wherein L in (IXa) and (IXb) is a displaceable group e.g. bromo, chloro,fluoro, mesyl or tosyl and wherein X is —O—,—S—, NR^(a) (optionally for—SO— and —SO₂— followed by the oxidation step of Process 1).

Compounds of formula (Va) and (Vb) where X is —SO— or —SO₂— may beprepared by oxidising the resulting compounds of formula (Va) and (Vb)from Scheme 2 where X is —S—.

Compounds of formula (Va) or (Vb) wherein X is —CH₂—, and n is 1, may beprepared according to Scheme 3.

The skilled person will appreciate that the above reaction scheme may bemanipulated to prepare compounds of formula (Va) or (Vb) where n is 2 or3.

Compounds of formula (XIIIa) or (XIIIb) maybe prepared by manipulationsknown to the skilled person of the processes described herein.

Compounds of formula (Vc), (VI), (VII), (VIII) and (XIV) arecommercially available compounds, or they are known in the literature,or they are prepared by standard processes known in the art.

-   Process 6): Compounds of formula (IXa) and (IXb) may be reacted with    thiols of formula (X) in the presence of base, for example an    inorganic base such as sodium carbonate or an organic base such as    Hunigs base, in the presence of a suitable solvent such as DMF or    THF at a temperature in the range of 0° C. to reflux.

Compounds of formula (IXa) and (IXb) may be prepared by any of theprocedures above for the preparation of compounds of formula (I), butwherein one of R⁴ and R⁵ is L.

Compounds of formula (X) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

-   Process 7) and Process 8) and Process 10): Esters of formula (XIa),    (XIb), (XIIa), (XIIb), (XVa) and (XVb) may be deprotected under    standard conditions such as those described below, for Example they    may be deprotected with sodium hydroxide in methanol at room    temperature.

Esters of formula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb) may beprepared by any of the procedures above for the preparation of compoundsof formula (I), but wherein R¹¹ or R¹⁵ or R²⁶ is an ester.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1999). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifuoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossess IBAT inhibitory activity. These properties may be assessed, forexample, using an in vitro test assay for studying the effect on bileacid uptake in IBAT-transfected cells (Smith L., Price-Jones M. J.,Hugnes K. T. and Jones N. R. A.; J Biomolecular Screening, 3, 227–230)or in vivo by studying the effect on radiolabelled bile acid absorptionin mice/rats (Lewis M. C., Brieaddy L. E. and Root C., J., J Lip Res1995, 36, 1098–1105).

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, will normally beadministered to a warm-blooded animal at a unit dose within the range5–5000 mg per square meter body area of the animal, i.e. approximately0.02–100 mg/kg, preferably 0.02–50 mg/kg, and this normally provides atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example 1–250 mg of active ingredient.Preferably a daily dose in the range of 1–50 mg/kg, particularly 0.1–10mg/kg is employed. However the daily dose will necessarily be varieddepending upon the host treated, the particular route of administration,and the severity of the illness being treated. Accordingly the optimumdosage may be determined by the practitioner who is treating anyparticular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, are effective IBAT inhibitors, and accordingly havevalue in the treatment of disease states associated with hyperlipidaemicconditions.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore, in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore, in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in theproduction of an IBAT inhibitory effect in a warm-blooded animal, suchas man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof hyperlipidaemic conditions in a warm-blooded animal, such as man.

Herein, where “the production of an IBAT inhibitory effect” or“producing an IBAT inhibitory effect” is referred to particularly thisrefers to the treatment of hyperlipidaemic conditions. In anotheraspect, “the production of an IBAT inhibitory effect” or “producing anIBAT inhibitory effect” refers to the treatment of dyslipidemicconditions and disorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). In anotheraspect “the production of an IBAT inhibitory effect” or “producing anIBAT inhibitory effect” refers to the treatment of different clinicalconditions such as atherosclerosis, arteriosclerosis, arrhythmia,hyper-thrombotic conditions, vascular dysfunction, endothelialdysfunction, heart failure, coronary heart diseases, cardiovasculardiseases, myocardial infarction, angina pectoris, peripheral vasculardiseases, inflammation of cardiovascular tissues such as heart, valves,vasculature, arteries and veins, aneurisms, stenosis, restenosis,vascular plaques, vascular fatty streaks, leukocytes, monocytes and/ormacrophage infiltration, intimal thickening, medial thinning, infectiousand surgical trauma and vascular thrombosis, stroke and transientischaemic attacks. In another aspect “the production of an IBATinhibitory effect” or “producing an IBAT inhibitory effect” refers tothe treatment of atherosclerosis, coronary heart diseases, myocardialinfarction, angina pectoris, peripheral vascular diseases, stroke andtransient ischaemic attacks in a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

The size of the dose required for the therapeutic or prophylactictreatment will necessarily be varied depending on the host treated, theroute of administration and the severity of the illness being treated. Aunit dose in the range, for example, 0.1–50 mg/kg preferably 0.1–10mg/kg is envisaged.

The IBAT inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. Accordingto this aspect of the invention there is provided a pharmaceuticalproduct comprising a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore and an additional IBAT inhibitory substance asdefined hereinbefore and an additional hypolipidaemic agent for theconjoint treatment of hyperlipidaemia.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an HMG Co-Areductase inhibitor, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductaseinhibitors, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are statins well known in the art.Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amimo]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof. Aparticular statin is atorvastatin, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof. A moreparticular statin is atorvastatin calcium salt. A further particularstatin is(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid, or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof. A more particular statin is rosuvastatincalcium salt.

In an additional aspect of the invention, the compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof may be administered in association with an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and/or a bile acid binderthereby avoiding a possible risk of excess of bile acids in colon causedby the inhibition of the ileal bile acid transport system. An excess ofbile acids in the visceral contents may cause diarrhoea. Thus, thepresent invention also provides a treatment of a possible side effectsuch as diarrhoea in patients during therapy comprising the compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof.

An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof will by its actiondecrease the endogenous cholesterol available for the bile acidsynthesis and have an additive effect in combination with the compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof on lipid lowering.

Suitable bile acid binders for such a combination therapy are resins,such as cholestyramine and cholestipol. One advantage is that the doseof bile acid binder might be kept lower than the therapeutic dose fortreatment of cholesterolaemia in single treatment comprising solely abile acid binder. By a low dose of bile acid binder any possible sideeffects caused by poor tolerance of the patient to the therapeutic dosecould also be avoided.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in simultaneous, sequential or separate administrationwith a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in simultaneous, sequential or separate administrationwith a bile acid binder.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder, in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a bile acid binder.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof and a bileacid binder.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof; in a    second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) a bile acid binder; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof; in a    second unit dosage form;-   c) a bile acid binder; in a third unit dosage form; and-   d) container means for containing said first, second and third    dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof, in a    second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) a bile acid binder, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof, in a    second unit dosage form; and-   c) a bile acid binder; in a third unit dosage form; and-   d) container means for containing said first, second and third    dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a bile acidbinder, in the manufacture of a medicament for use in the production ofan IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and a bile acid binder, inthe manufacture of a medicament for use in the production of an IBATinhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, a bile acidbinder, in the manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and a bile acid binder, inthe manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptableexcipient, with the simultaneous, sequential or separate administrationof an effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from:

-   -   a CETP (cholesteryl ester transfer protein) inhibitor, for        example those referenced and described in WO 00/38725 page 7        line 22–page 10, line 17 which are incorporated herein by        reference;    -   a cholesterol absorption antagonist for example azetidinones        such as SCH 58235 and those described in U.S. Pat. No. 5,767,115        which are incorporated herein by reference;    -   a MTP (microsomal transfer protein) inhibitor for example those        described in Science, 282, 751–54, 1998 which are incorporated        herein by reference;    -   a fibric acid derivative; for example clofibrate, gemfibrozil,        fenofibrate, ciprofibrate and bezafibrate;    -   a nicotinic acid derivative, for example, nicotinic acid        (niacin), acipimox and niceritrol;    -   a phytosterol compound for example stanols;    -   probucol;    -   an anti-obesity compound for example orlistat (EP 129,748) and        sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);    -   an antihypertensive compound for example an angiotensin        converting enzyme inhibitor, an angiotensin II receptor        antagonist, an andrenergic blocker, an alpha andrenergic        blocker, a beta andrenergic blocker, a mixed alpha/beta        andrenergic blocker, an andrenergic stimulant, calcium channel        blocker, a diuretic or a vasodilator;    -   insulin;    -   sulphonylureas including glibenclamide, tolbutamide;    -   metformin; and/or    -   acarbose;        or a pharmaceutically acceptable salt, solvate, solvate of such        a salt or a prodrug thereof, optionally together with a        pharmaceutically acceptable diluent or carrier to a warm-blooded        animal, such as man in need of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of formula(I) include but are not limited to, the following compounds: alacepril,alatriopril, altiopril calcium, ancovenin, benazepril, benazeprilhydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perndopfril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula (I) include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a PPAR alphaand/or gamma agonist, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/orgamma agonists, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are well known in the art. These includethe compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39,665, Expert Opinion on Therapeutic Patents, 10 (5), 623–634 (inparticular the compounds described in the patent applications listed onpage 634) and J Med Chem, 2000, 43, 527 which are all incorporatedherein by reference. Particularly a PPAR alpha and/or gamma agonistrefers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578,troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone,BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207,L-796449, L-165041, NN622/Ragaglitazar, BMS 298585 and GW 2433.Particularly a PPAR alpha and/or gamma agonist refers to(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoicacid and pharmaceutically acceptable salts thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In addition to their use in therapeutic medicine, the compounds offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, are also useful as pharmacologicaltools in the development and standardisation of in vitro and in vivotest systems for the evaluation of the effects of inhibitors of IBAT inlaboratory animals such as cats, dogs, rabbits, monkeys, rats and mice,as part of the search for new therapeutic agents.

Many of the intermediates described herein are novel and are thusprovided as a further feature of the invention. For Example compounds offormula (XIa), (XIb), (XIIa), (XIIb), (XVa) and (XVb) show IBATinhibitory activity when tested in the above referenced in vitro testassay and are thus claimed as a further feature of the invention.

Thus in a further feature of the invention, there is provided a compoundof formula (XIa), (XIb), (XIIa), (XIIb), (XVa) or (XVb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore according to a further aspect of the invention there isprovided a pharmaceutical composition which comprises a compound offormula (XIa), (XIb), (XIIa), (XIIb), (XVa) or (XVb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

According to an additional aspect of the present invention there isprovided a compound of the formula (XIa), (XIb), (XIIa), (XIIb), (XVa)or (XVb), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, as defined hereinbefore for use in amethod of prophylactic or therapeutic treatment of a warm-bloodedanimal, such as man.

Thus according to this aspect of the invention there is provided acompound of the formula (XIa), (XIb), (XIIa), (XIIb), (XVa) or (XVb), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (XIa), (XIb), (XIIa), (XIIb), (XVa) or(XVb), or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof as defined hereinbefore in the manufacture ofa medicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (XIa), (XIb), (XIIa), (XIIIb), (XVa) or(XVb), or a pharmaceutically acceptable salt, solvate, solvate of such asalt or a prodrug thereof as defined hereinbefore in the manufacture ofa medicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (XIa), (XIb), (XIIa), (XIIb), (XVa) or XVb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (XIa), (XIb), (XIIa), (XIIb), (XVa) or (XVb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated in the following non limitingexamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these examples may be usedwhere appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work up procedures were carried out after removal of residual solids    such as drying agents by filtration;-   (ii) all reactions were carried out under an inert atmosphere at    ambient temperature, typically in the range 18–25° C., with solvents    of HPLC grade under anhydrous conditions, unless otherwise stated;-   (iii) column chromatography (by the flash procedure) was performed    on Silica gel 40–63 μm (Merck);-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structures of the end products of the formula (I) were    generally confirmed by nuclear (generally proton) magnetic resonance    (NMR) and mass spectral techniques; magnetic resonance chemical    shift values were measured in deuterated CD₃OD (unless otherwise    stated) on the delta scale (ppm downfield from tetramethylsilane);    proton data is quoted unless otherwise stated; spectra were recorded    on a Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity    plus-600 MHz or on Varian Inova-500 MHz spectrometer; and peak    multiplicities are shown as follows: s, singlet; d, doublet; dd,    double doublet; t, triplet; tt, triple triplet; q, quartet; tq,    triple quartet; m, multiplet; br, broad; LCMS were recorded on a    Waters ZMD, LC column xTerra MS C₈(Waters), detection with a HP 1100    MS-detector diode array equipped; mass spectra (MS) (loop) were    recorded on VG Platform II (Fisons Instruments) with a HP-1100    MS-detector diode array equipped; unless otherwise stated the mass    ion quoted is (MH⁺);-   (vi) unless further details are specified in the text, analytical    high performance liquid chromatography (HPLC) was performed on Prep    LC 2000 (Waters), Kromasil C₈, 7 μm, (Akzo Nobel); MeCN and    de-ionised water 100 mM ammonium acetate as mobile phases, with    suitable composition;-   (vii) intermediates were not generally fully characterised and    purity was assessed by thin layer chromatography (TLC), HPLC,    infra-red (IR), MS or NMR analysis;-   (viii) where solutions were dried sodium sulphate was the drying    agent;-   (ix) where an “ISOLUTE” column is referred to, this means a column    containing 2 g of silica, the silica being contained in a 6 ml    disposable syringe and supported by a porous disc of 54 Å pore size,    obtained from International Sorbent Technology under the name    “ISOLUTE”; “ISOLUTE” is a registered trade mark;-   (x) the following abbreviations may be used hereinbefore or    hereinafter:

DCM dichloromethane; DMF N,N-dimethylformamide; TFA trifluoroaceticacid; TBTU o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate; EtOAc ethyl acetate; and MeCN acetonitrile.

Example 11,1-Dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepineand1,1-Dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine

(+−)-trans-1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-(carboxymethoxy)2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 1; 13 mg, 0.03 mmol) methyl (2R)-amino(phenyl)acetate (7.5 mg,0.037 mmol) and diisopropylethylamine (24 mg, 0.19 mmol) were dissolvedin DCM (1.5 ml). The mixture was stirred for 10 min and then TBTU (12mg, 0.037 mmol) was added and the reaction mixture was stirred for 30min. The solvent was removed under reduced pressure. The residue wasdissolved in ethanol (2 ml) and sodium hydroxide (2 mg) was added. Themixture was stirred for 30 min and the solvent was evaporated. Theresidue was purified by chromatography (DCM:EtOAc:AcOH, 100:10:3) givingthe title compound (5.5 mg, 32%). M/z: 565.3 (MH⁺), 563.2 (M⁻).

Example 21,1-Dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepineand1,1-Dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

An equal mixture of1,1-dioxo-3-(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepineand1,1-dioxo-3-(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 2; 27 mg, 0.040 mmol) were dissolved in 2 ml DCM.Trifluoroacetic acid (0.2 ml, 2.60 mmol) was added and the mixture wasstirred overnight at ambient temperature. The reaction mixture wasconcentrated under reduced pressure and then purified with preparativeHPLC using an MeCN/ammonium acetate buffer gradient (5/95 to 60/40) aseluent. The MeCN was evaporated and lyophilisation of the remainingsolution resulted in the title products in 69% yield (16 mg). NMR (400MHz, MeOD): 0.81 (t, 3H), 0.89 (t, 3H), 1.11–1.35 (m, 4H), 1.41–1.50 (m,1H), 1.52–1.62 (m, 1H), 1.74–1.84 (m, 1H), 2.17–2.28 (m, 1H), 3.34 (ABq,2H), 3.87 (ABq, 2H), 4.63–4.66 (m, 2H), 5.61 (s, 1H), 6.00 (s, 1H),6.59–6.64 (m, 1H), 6.95–7.01 (m, 1H), 7.27–7.44 (m, 10H), 7.64–7.67 (m,1H); m/z: 622 (M+1).

Example 33,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(carboxymethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 5; 50 mg, 0.10 mmol) was dissolved in DCM (3 ml). Lutidine(0.023 ml, 0.198 mmol), TBTU (38 mg, 0.118 mmol) and(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 4; 44 mg,0.167 mmol) were added successively. The mixture was stirred over nightat ambient temperature. The solution was concentrated to 1 ml and TFA(1.3 ml) was added. The mixture was concentrated after 1.5 h and theresidue was purified using preparative HPLC. A gradient from 40% to 60%of MeCN in 0.1 M ammonium acetate buffer was used as eluent.Lyophilisation yielded 39 mg (57%). NMR (400 MHz) 0.75 (t, 3H), 0.95 (t,3H), 1.2–1.4 (m, 6H), 1.75–1.9 (m, 1H), 2.2–2.4 (m, 1H), 3.35 (dd, 2H),3.85 (dd, 2H), 4.7–4.8 (m, 2H), 5.6 (s, 1H), 6.0 (d, 1H), 6.8 (d, 1H),7.25–7.5 (m, 10H), 7.6 (d, 1H); m/z: 700 (M) and 702 (M+2)²⁺.

Example 43,5-trans-1,1-Dioxo-3-(S)-3-ethyl-3-butyl-4-hydroxy-5-(S)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine3,5-trans-1,1-Dioxo-3-(R)-3-ethyl-3-butyl-4-hydroxy-5-(R)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine(Example 3; 14 mg, 0.02 mmol) was dissolved in 2 ml DCM.m-Chloroperoxybenzoic acid (5.5 mg, 0.022 mmol) was added and themixture was stirred for 30 min. The diastereomers of the title compoundwere separated using preparative HPLC on a C8 column. A gradient from30% to 60% of MeCN in 0.1 M ammonium acetate buffer was used as eluent.The two compounds were lyophilized and the first eluting diastereomerwas obtained in 5.4 mg and the second in 4.9 mg. M/z: 716 (M) and 718(M+2)²⁺. NMR (400 MHz) (diastereomer 1) 0.86 (t, 3H), 0.95 (t, 3H),1.1–1.4 (m, 3H), 1.4–1.55 (m, 2H), 1.68–1.8 (m, 1H), 2.0–2.2 (m, 2H),3.4 (dd, 2H), 3.88 (Abq, 2H), 4.76 (Abq, 2H), 5.6 (s, 1H), 6.45 (s, 1H),6.88 (s, 1H), 7.25–7.50 (m, 10H), 7.56 (s, 1H). NMR (diastereomer 2)(400 MHz) 0.87 (t, 3H), 0.95 (t, 3H), 1.1–1.4 (m, 3H), 1.4–1.55 (m, 2H),1.68–1.8 (m, 1H), 2.0–2.22 (m, 2H), 3.4 (dd, 2H), 3.82 (Abq, 2H), 4.76(Abq, 2H), 5.6 (s, 1H), 6.46 (s, 1H), 6.88 (s, 1H), 7.25–7.50 (m, 10H),7.57 (s, 1H).

Example 53,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(carboxymethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 6; 50 mg, 0.105 mmol) was dissolved in DCM (2 ml). 2,6-Lutidine(0.025 ml, 0.215 mmol), TBTU (45 mg, 0.140 mmol) andR)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 4; 43 mg,0.163 mmol) were added successively. The mixture was stirred for 2 hoursat ambient temperature. The solution was concentrated and theintermediate ester was purified by chromatography on silica usingDCM/EtOAc (9/1) as eluent. The solvent was evaporated to yield 45 mg(60%). M/z: 724. The ester was dissolved in 3 ml DCM and hydrolysed byaddition of TFA (1 ml). After 2 hours the mixture was concentrated andpurified using preparative HPLC. A gradient of MeCN from 40% to 60% in0.1 M ammonium acetate buffer was used as eluent. Lyophilisation yielded33 mg (80%). NMR (400 MHz): 0.75–0.85 (m, 3H), 0.85–0.95 (m, 3H),1.1–1.65 (m, 6H), 1.75–1.9 (m, 1H), 2.0 (s, 3H), 2.2–2.4 (m, 1H),3.1–3.55 (m, 2H), 3.85 (ABq, 2H), 4.6–4.8 (m, 2H), 5.6 (s, 1H),5.98–6.03 (m, 1H), 6.4 (s, 1H), 7.25–7.56 (m, 11H); m/z: 668.

Example 63,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepineammonia salt

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(carboxymethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 6; 33 mg, 0.070 mmol) was dissolved in DMF (3 ml).2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acidMethod 8; 23 mg, 0.084 mmol), N-methylmorpholine (0.025 ml, 0.227 mmol)and TBTU (27 mg, 0.084 mmol) were added successively and the mixture wasstirred overnight. The solvent was removed and the crude product waspurified using preparative HPLC. A gradient from 40% to 70% of MeCN in0.1 M ammonium acetate buffer was used as eluent. Lyophilisation yielded42 mg (80%) of the ammonium salt. NMR(400 MHz): 0.73–0.85 (m, 3H),0.85–0.98 (m, 3H), 1.1–1.7 (m, 6H), 1.75–1.9 (m, 1H), 2.0 (s, 3H),2.15–2.4 (m, 1H) 2.85–3.0 (m, 2H), 3.1–3.55 (m, 2H), 3.5–3.65 (m, 2H),4.6–4.8 (m, 2H), 5.35–5.39 (m, 1H), 5.98–6.05 (m, 1H), 6.4 (s, 1H), 6.75(d, 2H), 7.15–7.5 (m, 8H); m/z: 734.

Example 71,1-Dioxo-3-(S)-3-ethyl-3-butyl-5-(S)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepinediethylamine salt1,1-Dioxo-3-(R)-3-ethyl-3-butyl-5-(R)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepinediethylamine salt

The diasteromeric mixture of3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4benzothiazepine(Example 5; 17 mg, 0.026 mmol) was separated by chiral chromatography ona Chirobiotic V chiral stationary phase. Two columns (250×20 mm) inseries were used. A mobile phase consisting of 80% MeOH in water with0.1% Et₃N and 0.1% HOAc was used as eluent. The first elutingdiastereomer was collected in a 50 ml fraction and the solvent wasremoved under reduce pressure. Et₃N remained according to NMR-analysisand the diastereomer was purified by chromatography over 0.5 g SiO₂using DCM/MeOH (9/1) as eluent. The solvent was removed and the productwas dissolved in water and some MeCN. Lyophilisation yielded a whitesolid, which was dissolved in MeOH and filtered. A second lyophilisationyielded the diastereomer as the Et₃N salt in 1 mg (4%). M/z: 668. NMR(HOAc-d4) was consistent with Example 5. The e.e. was determined as 99%.The second eluting diastereomer was collected in a 200 ml fraction andthe solvent was removed under reduced pressure. The residue was purifiedusing preparative HPLC on a C8 column. A gradient from 35% to 50% MeCNin 0.1 M ammonium acetate was used as eluent. Lyophilisation yielded thediastereomer as the Et₃N salt in 3 mg (17 mg). M/z: 668. The e.e. wasdetermined as 97%.

Preparation of Starting Materials

The starting materials for the Examples above are either commerciallyavailable or are readily prepared by standard Methods from knownmaterials. For Example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Method 1

(+−)-trans-1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-(carboxymethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3,4,5-tetrahydro-1,4benzothiazepine(prepared according to WO/9605188; 83 mg, 0,22 mmol), ethyl bromoacetate(55 mg, 0.33 mmol) and sodium carbonate (70 mg, 0.66 mmol) inacetonitrile (3 ml) were warmed to reflux for 40 hours. The solvent wasremoved under reduced pressure and the crude product was dissolved inethanol (4 ml). Sodium hydroxide (0.1 g) was added and the mixture waswarmed to reflux for 1 hour. The solvent was removed under reducedpressure and the residue was partitioned between DCM and 2 M aceticacid. The organic layer was dried over sodium sulphate and the solventwas removed under reduced pressure. The residue was purified bychromatography (EtOAc: formic acid, 500:1) to give 61 mg (64%) of thetitle compound. NMR (500 MHz, CDCl₃): 0.86 (t, 3H), 0.92 (t, 3H),1.0–1.05 (m, 1H), 1.2–1.4 (m, 3H), 1.6–1.75 (m, 2H), 1.85–1.95 (m, 1H),2.38–2.47 (m, 1H), 3.45 (s, 2H), 4.5 (s, 2H), 6.17 (s, 1H), 6.75 (d,1H), 6.86 (dd, 1H), 7.37–7.5 (m, 5H), 7.64 (d, 1H).

Method 2

1,1-Dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5phenyl-8-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;and

1,1-Dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-(N-{(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

(+−)-trans-1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-(carboxymethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 1; 17.5 mg, 0.041 mmol) was dissolved in DCM (3 ml).2,6-Lutidine (0.010 ml, 0.086 mmol), TBTU (16.4 mg, 0.051 mmol) and(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 4; 16.3mg, 0.062 mmol) were added successively. The mixture was stirred for 1hour at ambient temperature. The solution was concentrated and the crudeproduct was purified by chromatography on silica using DCM/EtOAc (8/2)as eluent. The solvent was evaporated and the title products wereobtained in 98% yield (27 mg). M/z: 678 (M+1).

Method 3

(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine

(2R)-{[(Benzyloxy)carbonyl]amino}(phenyl)acetic acid (10 g, 35.0 mmol)and t-butylglycine hydrochloride (6.3 g, 37.4 mmol) were dissolved inDCM (200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). After stirring 5 minat 0° C. TBTU (12.4 g, 38.6 mmol) was added and stirring was continuedfor 1.5 hours at 0° C. and 3.75 hours at room temperature. The reactionmixture was washed with water (2×100 ml), dried (MgSO₄) and purifiedwith flash chromatography (DCM:EtOAc 7:1→5:1) to give the title compound(13 g, 94%). NMR (500 MHz, CDCl₃): 1.45 (s, 9H), 3.84 (d, 1H), 4.00 (dd,1H), 5.10 (m, 2H), 5.28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1H),7.30–7.44 (m, 10H).

Method 4

(R)-α-[N-(t-Butoxycarbonylmethyl)carbamoyl]benzylamine

(R)-N-Benzyloxycarbonyl-α-[N-(t-butoxycarbonylmethylcarbamoyl]benzylamine(Method 3; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) andtoluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation wasperformed at atmospheric pressure for 5.5 hours at room temperature. Thereaction mixture was filtered through diatomaceous earth and thesolvents were evaporated to give the title compound (8.4 g, 99%). NMR(600 MHz, CDCl₃): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31–7.42(m, 5H), 7.51 (brs, 1H).

Method 5

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(carboxymethoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine

The title compound was prepared as described in Method 6 starting from(+/−)-trans-7-bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol1,1-dioxide (WO96/05188; 81 mg, 0.18 mmol). The intermediate ethyl esterwas obtained in 94% yield (m/z: 538(M) and 540(M+2)). The product wasobtained in 50 mg (58%). NMR 0.75 (t, 3H), 0.95 (t, 3H), 1.2–1.45 (m,6H), 1.75–1.9 (m, 1H), 2.2–2.4 (m, 1H), 3.35 (dd, 2H), 4.8 (s, 2H), 6.0(s, 1H), 6.8 (s, 1H), 7.3–7.5 (m, 5H), 7.55 (s, 1H); m/z: 510 (M) and512 (M+2)²⁺.

Method 6

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(carboxymethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine

The title compound was prepared from3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,4-benzothiazepine(Method 7; 153 mg, 0.36 mmol) using the procedure described in Method 1.The intermediate ethyl ester was extracted between diluted HCl and DCM.The DCM phase was washed with brine, dried with Na₂SO₄ and concentrated.M/z 506. The crude product was dissolved in THF/H₂O (3/1; 4 ml) and LiOH(22 mg, 0.91 mmol) was added. The mixture was stirred for 2 h and thesolvent was removed under reduced pressure. The crude product waspurified using preparative HPLC. A gradient from 40% to 60% MeCN in 0.1M ammonium acetate buffer was used as eluent. The MeCN was removed underreduced pressure and the remaining aqueous solution was acidified using5% HCl and was then extracted with DCM. The DCM layer was dried withNa₂SO₄ and concentrated. The crude product was co-evaporated withdiethyl ether. The obtained crystals were filtered off and dried. Mass:158 mg (91%). NMR 0.75 (t, 3H), 0.9 (t, 3H), 1.1–1.7 (m, 6H), 1.7–1.9(m, 1H), 2.0 (s, 3H), 2.2–2.4 (m,1H), 3.3 (dd, 2H), 4.75 (s, 2H) 6.0 (s,1H), 6.4 (s, 1H), 7.3–7.5 (m, 6H); m/z: 478.

Method 7

3,5-trans-1,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,4-benzothiazepine

(+/−)-trans-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide (prepared according to WO 96/05188; 300 mg, 0.64 mmol) wasdissolved in 5 ml DMF under N₂(g)-atmosphere. Sodium thiomethylate (150mg, 2.14 mmol) was added and the mixture was heated to 110° C. for 2 h.The solvent was removed under reduced pressure and the residue wasextracted between 5% HCl and EtOAc. The organic phase was washed withbrine, dried with Na₂SO₄ and concentrated. The product was purifiedusing preparative HPLC. A gradient from 40% to 100% of MeCN in 0.1 Mammonium acetate buffer was used as eluent. Lyophilisation yielded 153mg, 57%. M/z: 420.

Method 8

2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid

N-Boc-(D)-4hydroxyphenylglycine (1.00 g, 3.21 mmol) was dissolved in DMF(5 ml) and tetrabutylammonium taurine (2.36 g, 6.42 mmol) was addedtogether with additional DMF (5 ml). The resulting suspension was cooledon ice and TBTU (1.24 g, 3.85 mmol) was added. The ice bath was removedafter 30 min and the mixture was stirred for 2 hours before it wasfiltered and concentrated. TFA in DCM (20%, 20 ml) was added and thereaction mixture was stirred over night. Ethanol (20 ml) was added andthe solvents evaporated. The crude product was refluxed in ethanol (100ml) for 1 hour. Filtration yielded the pure title compound as a whitesolid, 626 mg (71%). NMR (DMSO-d₆): 2.4–2.6 (m, 2H), 3.2–3.4 (m, 2H),4.79 (s, 1H), 6.78 (d, 2H),7.23 (d, 2H), 8.22 (t, 1H), 8.4 (brs, 3H),9.7 (s, 1H).

1. A compound of formula (I):

wherein: One of R¹ and R² are selected from hydrogen, C₁₋₆alkyl orC₂₋₆alkenyl and the other is selected from C₁₋₆alkyl or C₂₋₆alkenyl;R^(y) is selected from hydrogen, hydroxy, C₁₋₆alkyl, C₁₋₄alkoxy andC₁₋₆alkanoyloxy; R^(z) is selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; v is 0–5; one of R⁴ and R⁵ is a group offormula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶; X is —O—,—N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen orC₁₋₆alkyl and b is 0–2; Ring A is aryl or heteroaryl; wherein Ring A isoptionally substituted by one or more substituents selected from R¹⁷; R⁷is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸; R⁸is hydrogen or C₁₋₄alkyl; R⁹ is hydrogen or C₁₋₄alkyl; R¹⁰ is hydrogen,C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ is optionallysubstituted by one or more substituents selected from R¹⁹; R¹¹ iscarboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB):

 wherein: Y is —N(R^(x))—, —N(R^(x))C(O)—, —O—, and —S(O)a-; wherein ais 0–2 and R^(x) is hydrogen or C₁₋₄alkyl; R¹² is hydrogen or C₁₋₄alkyl;R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₆alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl; or R¹⁵ is agroup of formula (IC):

 wherein: R²⁴ is selected from hydrogen or C₁₋₄alkyl; R²⁵ is selectedfrom hydrogen, C₁₋₄alkyl, carbocyclyl, heterocyclyl or R^(27;) whereinsaid C₁₋₄alkyl, carbocyclyl or heterocyclyl may be independentlyoptionally substituted by one or more substituents selected from R²⁸;R²⁶ is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl,—P(O)(OR^(g))(OR^(h)), —P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or—P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) are independently selectedfrom C₁₋₆alkyl; p is 1–3; wherein the values of R¹³ may be the same ordifferent; q is 0–1; r is 0–3; wherein the values of R¹⁴ may be the sameor different; m is 0–2; wherein the values of R¹⁰ may be the same ordifferent; n is 1–3; wherein the values of R⁷ may be the same ordifferent; z is 0–3; wherein the values of R²⁵ may be the same ordifferent; R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N—(C₁₋₄alkyl)sulphamoyl and N,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷and R¹⁸ may be independently optionally substituted on carbon by one ormore R²¹; or a pharmaceutically acceptable salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof. 2.A compound of formula (I) as claimed in claim 1 wherein one of R¹ and R²is ethyl and the other is butyl or a pharmaceutically acceptable salt,or an in vivo hydrolysable ester formed on an available carboxy orhydroxy thereof, or an in vivo hydrolysable amide formed on an availablecarboxy thereof.
 3. A compound of formula (I) as claimed in claim 1wherein R^(y) is hydrogen or hydroxy or a pharmaceutically acceptablesalt, or an in vivo hydrolysable ester formed on an available carboxy orhydroxy thereof, or an in vivo hydrolysable amide formed on an availablecarboxy thereof.
 4. A compound of formula (I) as claimed in claim 1wherein v is 0 or a pharmaceutically acceptable salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof. 5.A compound of formula (I) as claimed in claim 1 wherein R³ and R⁶ arehydrogen or a pharmaceutically acceptable salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof. 6.A compound of formula (I) as claimed in claim 1 wherein R⁴ is hydrogen,halo or C₁₋₄alkylS(O)_(a) wherein a is 0 or a pharmaceuticallyacceptable salt, or an in vivo hydrolysable ester formed on an availablecarboxy or hydroxy thereof, or an in vivo hydrolysable amide formed onan available carboxy thereof.
 7. A compound of formula (I) as claimed inclaim 1 wherein R⁵ is a group of formula (IA) (as depicted in claim 1);wherein X is —O—; Ring A is phenyl or 4-hydroxyphenyl; R⁷ is hydrogen;R⁸ is hydrogen; R⁹ is hydrogen; R¹¹ is carboxy; or R¹¹ is a group offormula (IB) (as depicted above); wherein R¹² is hydrogen; R¹³ hydrogen;R¹⁵ is carboxy or sulpho; p is 1 or 2; q is 0; r is 0; m is 0; and n is1; or a pharmaceutically acceptable salt, or an in vivo hydrolysableester formed on an available carboxy or hydroxy thereof, or an in vivohydrolysable amide formed on an available carboxy thereof.
 8. A compoundof formula (I) as claimed in claim 1 wherein R¹ and R² are C₁₋₄alkyl; vis 0; R^(y) is hydrogen or hydroxy; R³ and R⁶ are hydrogen; R⁴ ishydrogen, halo or C₁₋₄alkylS(O)_(a) wherein a is 0; R⁵ is a group offormula (IA) (as depicted above); wherein X is —O—; Ring A is aryl;wherein Ring A is optionally substituted by one or more substituentsselected from R¹⁷; R⁷ is hydrogen; R⁸ is hydrogen; R⁹ hydrogen; R¹¹ iscarboxy; or R¹¹ is a group of formula (IB) (as depicted above); whereinR¹² hydrogen; R¹³ hydrogen; R¹⁵ is carboxy or sulpho; p is 1 or 2; q is0; r is 0; m is 0; n is 1; and R¹⁷ is hydroxy; or a pharmaceuticallyacceptable salt, or an in vivo hydrolysable ester formed on an availablecarboxy or hydroxy thereof, or an in vivo hydrolysable amide formed onan available carboxy thereof.
 9. A compound of formula (I) as claimed inclaim 1 selected from1,1-dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine;1,1-dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,4-benzothiazepine;1,1-dioxo-3(R)-3-butyl-3-ethyl-5-(R)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;1,1-dioxo-3(S)-3-butyl-3-ethyl-5-(S)-5-phenyl-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;3,5-trans-1,1-dioxo-3-(S)-3-ethyl-3-butyl-4-hydroxy-5-(S)-5-phenyl-7-bromo-8-(N-{(R)-α-N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine3,5-trans-1,1-dioxo-3-(R)-3-ethyl-3-butyl-4-hydroxy-5-(R)-5-phenyl-7-bromo-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepine;3,5-trans-1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepineammonia salt;1,1-dioxo-3-(S)-3-ethyl-3-butyl-5-(S)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepinediethylamine salt; and1,1-dioxo-3-(R)-3-ethyl-3-butyl-5-(R)-5-phenyl-7-methylthio-8-(N-{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,4-benzothiazepinediethylamine salt; or a pharmaceutically acceptable salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof.10. A process for preparing a compound of formula (I) or apharmaceutically acceptable salt, or an in vivo hydrolysable esterformed on an available carboxy or hydroxy thereof, or an in vivohydrolysable amide formed on an available carboxy thereof, as claimed inclaim 1, which process comprises of: Process 1): oxidising abenzothiazepine of formula (II):

Process 2): for compounds of formula (I) wherein X is —O—, —NR^(a) or—S—; reacting a compound of formula (IIIa) or (IIIb):

 with a compound of formula (IV):

 wherein L is a displaceable group; Process 3): reacting an acid offormula (Va) or (Vb):

 or an activated derivative thereof; with an amine of formula (VI):

Process 4): for compounds of formula (I) wherein R¹¹ is a group offormula (IB); reacting a compound of formula (I) wherein R¹¹ is carboxywith an amine of formula (VII):

Process 5): for compounds of formula (I) wherein R¹¹ is a group offormula (IB) and R¹⁵ is a group of formula (IC) reacting a compound offormula (I) wherein R¹⁵ is carboxy with an amine of formula (VIII):

Process 6) for compounds of formula (I) wherein one of R⁴ and R⁵ areindependently selected from C¹⁻⁶alkylthio optionally substituted oncarbon by one or more R¹⁶; reacting a compound of formula (IXa) or(IXb):

 wherein L is a displaceable group; with a thiol of formula (X):R^(m)—H  (X)  wherein R^(m) is C¹⁻⁶alkylthio optionally substituted oncarbon by one or more R¹⁶; Process 7): for compounds of formula (I)wherein R¹¹ is carboxy; deprotecting a compound of formula (XIa):

 wherein R^(x) together with the —OC(O)— group to which it is attachedforms an ester; Process 8): for compounds of formula (I) wherein R¹¹ isa group of formula (IB) and R¹⁵ is carboxy; deprotecting a compound offormula (XIIa):

 wherein R^(x) together with the —OC(O)— group to which it is attachedforms an ester; Process 9): for compounds of formula (I) wherein R¹¹ isa group of formula (IB) and Y is —N(R^(x))C(O)—; reacting an acid offormula (XIIIa):

 or an activated derivative thereof; with an amine of formula (XIV):

or Process 10): for compounds of formula (I) wherein R¹¹ is a group offormula (IB), R¹⁵ is a group of formula (IC) and R²⁶ is carboxy;deprotecting a compound of formula (XVa):

 nwherein R^(x) together with the —OC(O)— group to which it is attachedforms an ester; and thereafter optionally: i) converting a compound ofthe formula (I) into another compound of the formula (I); ii) removingany protecting groups; iii) forming a pharmaceutically acceptable salt,or forming an in vivo hydrolysable ester on an available carboxy orhydroxy thereof, or forming an in vivo hydrolysable amide formed on anavailable carboxy.
 11. A pharmaceutical composition which comprises acompound of formula (I), or a pharmaceutically acceptable salt, or an invivo hydrolysable ester formed on an available carboxy or hydroxythereof, or an in vivo hydrolysable amide formed on an available carboxythereof, as claimed in any one of claims 1 to 9, in association with apharmaceutically-acceptable diluent or carrier.